The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences--e.g., gastrointestinal irritation and the like--are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration.
Relatively recent advances in transdermal drug delivery have enabled effective administration of a variety of drugs through the skin. These advances include the development of a number of skin penetration enhancing agents, or "permeation enhancers," to increase the permeability of the skin or mucosal tissue, as well as non-chemical modes for facilitating transdermal delivery, e.g., the use of iontophoresis, electroporation or ultrasound. Nevertheless, the number of drugs that can be safely and effectively administered through the skin, without concomitant problems such as irritation or sensitization, remains limited.
The present invention is directed to transdermal drug delivery using "high capacity" hydrogel drug reservoirs into which a far greater quantity of drug may be present than possible with conventional transdermal systems. Thus, greater quantities of drug may be delivered, at higher fluxes. In addition, the high capacity drug reservoirs, also reduce or in some cases eliminate the need for permeation enhancers. Further, smaller transdermal patches may be made using the inventive technology, i.e., patches that are at least as effective as prior patches in terms of overall drug release and drug flux, but are significantly reduced in terms of size.
While hydrogels have been described as potentially useful in drug delivery systems (see, e.g., P. I. Lee, J. Controlled Release 2:277-288 (1985)), their use in transdermal systems, and particularly the use of polyurethane hydrogels, is believed to be novel. None of the art of which applicants are aware describes transdermal drug delivery system having high capacity, polyurethane hydrogel drug reservoirs, nor does the art disclose methods for manufacturing such systems as disclosed and claimed herein.
The invention may be used to deliver a wide variety of drugs. For example, the present drug delivery systems may be used in the transdermal administration of 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno2,3-b!1,5!benzodiazepine, also known as "olanzapine." The drug is described in U.S. Pat. No. 5,229,382 to Chakrabarti et al., issued Jul. 20, 1993, and assigned to Lilly Industries Limited. Reference may be had thereto for any information concerning methods for synthesizing or using olanzapine not explicitly included herein. ##STR1## Olanzapine is an antagonist of dopamine at the D-1 and D-2 receptors, and in addition has antimuscarinic anticholinergic properties and antagonist activity at 5HT-2 receptor sites and at noradrenergic .alpha.-receptors (Moore et al., J. Pharmacol. Exp. Ther. 262(2):545-551 (1992)). The drug has relaxant, anxiolytic and anti-emetic properties, and, as explained in the Chakrabarti et al. patent, is useful in the treatment of psychosis, acute mania and mild anxiety states, and is particularly useful in the treatment of schizophrenia and schizophreniform illnesses.
Currently, olanzapine is administered orally or by injection. While the drug has been established as an effective antipsychotic agent, drug non-compliance is a serious problem, and is believed to account for approximately one-third of all short-stay hospital costs. Transdermal administration of olanzapine or a pharmaceutically acceptable salt thereof, significantly enhances patient compliance by providing an advanced delivery system useful for administering the drug over an approximately three- to seven-day period. There are a number of other advantages to administering olanzapine transdermally as well: gastrointestinal and other side effects associated with oral administration are substantially avoided; continuous delivery provides for sustained blood levels; the transdermal patch is easily removable if any side effects do occur; and the likelihood of patient acceptance is significantly improved. In general, steady-state, transdermal delivery of the drug seems to provide a far better side effect profile overall than is associated with oral administration.
The present systems are also useful in the transdermal administration of steroid drugs, including androgenic agents. Particular compounds of interest are testosterone and pharmaceutically acceptable esters and derivatives thereof. Such agents are useful in a variety of applications, e.g., in treating hypogonadism, hypopituitarism, Addison's disease, impotence, male infertility disorders, anemia, and in male hormone replacement therapy. The invention also involves the transdermal administration of androgenic agents in combination with estrogens, in treating, for example, menopause, osteoporosis, or other conditions for which estrogen-androgen combination therapy is indicated.
Transdermal delivery of androgens, alone or in combination with estrogenic agents, has been described. See, e.g., U.S. Pat. No. 4,704,282 to Campbell et al., U.S. Pat. No. 4,867,982 to Campbell et al., U.S. Pat. No. 5,094,857 to Luderschmidt, U.S. Pat. No. 5,152,997 to Ebert et al., U.S. Pat. No. 5,460,820 to Ebert et al., and PCT Publication No. WO95/03764. In contrast to prior systems for administering these drugs transdermally, however, the present invention is directed transdermal systems in which the androgenic agent is contained within drug reservoirs into which a far greater quantity of drug may be loaded than possible with conventional transdermal systems. As explained above, such systems provide a number of advantages, including delivery of greater quantities of drug, at higher fluxes, reduction of patch size, and the like.
The following references are of interest insofar as they pertain to the subject matter of the invention:
U.S. Pat. No. 4,438,258 to Graham describes a wound dressing of a hydrogel comprised of a polymerizable cyclic thioether and at least one hydrophilic homo- or copolymer, which may contain a urethane functionality.
U.S. Pat. No. 4,644,033 to Gnanou et al. relates to contact lenses of polyurethane hydrogels formed by crosslinking polyoxyethylene with a polyfunctional isocyanate.
U.S. Pat. No. 5,160,328 to Cartmell et al. describes a self-adhesive bandage having a polyurethane hydrogel layer stated to be suitable for absorbing bodily fluids. The hydrogel is formed from a polyhydric alcohol, an isophoronediisocyanate-terminated prepolymer, a polyethylene oxide based diamine, sodium chloride and water.
U.S. Pat. No. 5,352,508 to Cheong relates to wound dressings comprising a polyurethane matrix formed by reacting a polyisocyanate with an excess of a polyhydroxy compound.